tbuckley/cabot-search huggingface dataset:
PATH-18. SHOULD LEPTOMENINGEAL DISSEMINATION (LMD) AT DIAGNOSIS WITH AN H3K27M MUTATION BE ENOUGH TO BE CONSIDERED A DIFFUSE MIDLINE GLIOMA (DMG) H3K27M ALTERED?
Authors: Janet La, Tresa McGranahan
Journal: Neuro-Oncology (2022)

Abstract Currently diffuse midline glioma (DMG) H3K27M-altered is defined as a diffuse, infiltrating midline glioma with an altered H3K27M pathway. A number of brain tumors have been reported with alterations in H3K27M that do not meet DMG diagnostic criteria and the clinical significance of H3K27M alteration in these tumors is unknown. Patients with extensive leptomeningeal disease often do not undergo large tumor resections and as a result there is limited tissue available for histologic evaluation. We present two patients who presented with leptomeningeal disease (LMD) and given extent of disease were only able to undergo subtotal resection. In both of these cases, the pathology specimens were found to have H3K27M alterations by immunohistochemistry but did not meet the diagnostic criteria for DMG due to the lack of histologic evidence of infiltration. Both patients were young women (age 23 and 28) who presented with new headaches, nausea, and vomiting and were found to have extensive LMD. Both were treated initially with proton craniospinal radiation and concurrent temozolomide. Within 1 year of initial diagnosis, both had radiographic and clinical progression of both parenchymal and LMD. Despite aggressive treatment, both patients clinically declined and transitioned to hospice within 2 years of diagnosis. Our understanding of the H3K27M altered pathway at this time is limited, and the significance of this mutation is unknown in tumors where an infiltrating component is not captured histologically. While LMD is rare at initial presentation of DMG, it is seen commonly at disease progression. We propose that the presence of H3K27M alteration with known leptomeningeal disease at diagnosis should be considered grade 4 histology and DMG for the purposes of prognostication and clinical trial consideration. Given ability to detect this mutation in CSF sampling, this may spare patients from surgical intervention and expedite time to treatment.
CTIM-10. A PHASE II STUDY OF RETIFANLIMAB (PD-1 INHIBITOR) IN COMBINATION WITH BEVACIZUMAB AND HYPOFRACTIONATED RADIOTHERAPY FOR RECURRENT GLIOBLASTOMA: NCT03532295
Authors: Omar Butt, Jiayi Huang, Jingqin Luo, Yu Tao, Roy Strowd, Deanna Hissim, Sani Kizilbash, Christopher Abraham, George Anstass, Tanner Johanns, Albert Kim, Matthew Ciorba, Milan G Chheda, Jian Campian
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Immunotherapies targeting PD-1 in recurrent glioblastoma (rGBM) have shown limited activity. We hypothesize combining therapies targeting immunosuppressive pathways with cytotoxic and antiangiogenic therapies will improve survival. This nonrandomized, noncomparative Phase II study examines safety and efficacy of an anti-PD-1 monoclonal antibody (retifanlimab), hypofractionated radiotherapy (HFRT), and bevacizumab, with or without an IDO1 inhibitor (epacadostat), in patients with rGBM. METHODS This is an open-label Phase II study of two regimens. Regimen A examines retifanlimab (500mg IV Q4W) + bevacizumab (10mg/kg IV Q2W) + HFRT (3.5Gy/day x 10) in patients with IDH1/2-WT rGBM. Regimen B adds epacadostat. Key inclusions include dexamethasone ≤ 4 mg/day and reirradiation candidacy. The primary endpoint is overall survival (OS) probability at 9 months (OS-9). An increase of OS-9 from 38% (bevacizumab alone) to 60% was considered clinically relevant and required 24 efficacy evaluable patients. RESULTS Regimen A accrual is complete; interim results are as follows: 26 rGBM enrolled, with 24 evaluable [median age 64.2 years (42.1-81.8); 29% female; 29% MGMT promotor methylated; 33.3% with multi-focal disease; median KPS 90 (70-100); median baseline dexamethasone 0 mg (0-4) and ALC 1,000 cells/µl (300-3,700)]. Patients received a median of 6 cycles as of May 2022 (2-24). Median follow-up is 16.0 months. Interim median PFS is 7.0 months (95%CI: 4.5~11.1) and median OS is 12.2 months (95%CI 7.1~18.0). Regimen A met primary endpoint with OS-9 of 67% (95%CI: 44~82%). Overall response rate is currently 58% (95%CI: 36.94~77.2%). There were five possible immune-related grade 3+ toxicities to date (n = 1 each colitis, vomiting, and seizure; n = 2 diarrhea). Regimen B is enrolling. CONCLUSIONS Interim analysis suggests combination retifanlimab, HFRT, and bevacizumab in rGBM is generally well-tolerated, with encouraging OS and PFS at the time of submission. Correlative analysis is ongoing and will be presented at the meeting.
SURG-29. CAN NEOADJUVANT CHEMOTHERAPY INCREASE EXTENT OF RESECTION IN DIFFUSE LOWER-GRADE GLIOMA?
Authors: Piravin Ramakrishnan, Saad Moughal, William Bolton, John Gooden, Paul Chumas, Ryan Mathew
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Maximal safe surgical resection remains front-line treatment for diffuse lower-grade gliomas (DLGGs). Greater extent of resection (EOR) can delay transformation, control seizures, and improve survival. EOR is limited by the infiltrative nature of DLGGs and eloquent brain location preponderance. We investigated the role of neoadjuvant chemotherapy in tumour volume reduction (TVR) for cases in which a meaningful EOR was deemed unachievable. METHODS Retrospective review (2000-2020) of patients in a large tertiary UK brain tumor centre who serendipitously underwent management that did or could mimic a neoadjuvant chemotherapy pathway. Inclusion criteria: &amp;gt;18 years at diagnosis; histologically-proven WHO grade 2 supratentorial glioma; received chemotherapy alone after biopsy then +/- debulking. Tumour volume delta +/- EOR were calculated on serial MRI T2/FLAIR sequences using a semi-automated quantitative analysis tool (Smartbrush, BrainLab® AG). RESULTS Group 1 (neoadjuvant chemotherapy and then surgery, n=4): debulking was considered unachievable initially but then possible post-chemotherapy. Median TVR post-chemotherapy was 16.90% (range 0.45–64.90%). Mean EOR was 68.67% (33.72–100%). Median overall survival (OS) and progression free survival (PFS) were 85 (18–154) and 62 (13–153) months, respectively. Group 2 (biopsy followed by chemotherapy alone, n=7): debulking was considered unachievable initially. Median TVR post-chemotherapy was 25.68% (-294.95–46.02%, one patient progressed during chemotherapy). Median OS and PFS were 92 (6–135) and 27 (3–80) months, respectively. On re-review, and based on Group 1 results, some Group 2 patients may have been able to undergo debulking with meaningful EOR post-chemotherapy. CONCLUSIONS Chemotherapy can have a significant impact on reducing tumour volumes, such that cases initially deemed unsuitable for debulking may be converted into those in which a meaningful EOR can be achieved. Larger, multicentre, retrospective studies, and prospective trials are needed to determine the role of chemotherapy as a neoadjuvant tool in the management of DLGGs.
CTNI-02. PRECLINICAL DATA AND INITIAL CLINICAL EXPERIENCE IN THE PHASE 1/2A DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN LEPTOMENINGEAL METASTASES [LM]: THE RESPECT-LM TRIAL
Authors: Andrew Brenner, Michael Youssef, Norman LaFrance, Marc Hedrick, Ande Bao, William Phillips, Toral Patel, Jeffrey Weinberg, John Floyd
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Leptomeningeal metastases (LM) is a clinical complication that occurs when cancer cells invade the leptomeninges and cerebrospinal fluid of patients with malignant tumors. Once diagnosed, limited treatment options exist, and survival is poor. Rhenium-186 Nanoliposome (186RNL) is a liposomal encapsulated beta emitter with a short path length of 1.8 mm, thereby allowing high specific activity brachytherapy with limited exposure to surrounding tissues. METHODS Preclinical efficacy was assessed using C6-Luc glioma cells in Wistar rats or MDA-MB-231 in Athymic Nude Rats via intraventricular injection. At 15 days post inoculation the animals were treated with 0.69 mCi of 186RNL. Absorbed doses were assessed with gamma camera imaging at 0h, 24h, and 48h post-treatment. Tumor growth was assessed by luciferase bioluminescence. A multicenter phase 1/2a dose (3 + 3 design) escalation trial was then initiated with 186RNL in LM patients to determine the maximum feasible dose, overall response rate (ORR) and overall survival distribution. RESULTS A significant difference in survival between the control and treatment groups (n = 8 each) was observed in the C6/Wistar model at 2 weeks post treatment, with 50% survival in the control group and 100% survival in the treatment group (p = 0.0087). Similar efficacy was observed in the MDA-MB-236/Athymic model. Thus far two patients have received 186RNL with 6.6 mCi in 5ml via Ommaya reservoir. Post treatment imaging shows full CSF distribution by 4 hours and persistence of activity through 7 days following administration. The dose was well-tolerated with no related AEs through day 56 following treatment. CSF cell count by BioCept analysis was reduced by &amp;gt; 90% with durability through day 28. CONCLUSION Intraventricular delivered 186RNL is promising for treatment of LM, with very early evidence of efficacy in patients. Enrollment is ongoing.
NIMG-68. IMAGING PHOSPHOLIPID BIOSYNTHESIS ENABLES NON-INVASIVE ASSESSMENT OF BRAIN TUMOR RESPONSE TO THERAPY
Authors: Celine Taglang, Georgios Batsios, Meryssa Tran, Anne Marie Gillepspie, Pavithra Viswanath
Journal: Neuro-Oncology (2022)

Abstract Elevated phospholipid biosynthesis is a metabolic hallmark of cancer. Due to the high membrane turnover associated with uncontrolled proliferation, tumor cells invariably upregulate phospholipid biosynthesis. Choline is a dietary nutrient that is phosphorylated to phosphocholine (PC) and subsequently incorporated into phosphatidylcholine, which is the primary membrane phospholipid in mammalian cells. Choline kinase α (CKα) is the key enzyme in this pathway and its expression is elevated in most cancers. Identifying non-invasive methods of imaging CKα activity, can, therefore, enable assessment of tumor burden and response to therapy. Deuterium magnetic resonance spectroscopy (DMRS) following administration of 2H-labeled substrates recently emerged as a simple, robust, clinically translatable method of assessing metabolic activity in vivo. The goals of the current study were to determine whether DMRS-based assessment of PC production from [2H9]-choline tracks CKα activity and to establish the utility of [2H9]-choline for glioma imaging in vivo. First, we show that [2H9]-choline metabolism to PC can be observed in live patient-derived glioma cells (GBM6 and BT88). Silencing CKα abrogates PC production from [2H9]-choline in both GBM6 and BT88 models, thereby confirming that [2H9]-choline provides a readout of CKα activity. Next, we examined the ability of [2H9]-choline to monitor tumor burden and response to therapy in vivo. [2H9]-choline metabolism to PC can be observed in mice bearing orthotopic patient-derived GBM6 or BT257 tumors, but not in tumor-free healthy controls. Importantly, following treatment of mice bearing orthotopic BT257 tumors with temozolomide, which is standard of care for glioma patients, PC production from [2H9]-choline is reduced at early timepoints when changes in tumor volume cannot be detected by anatomical imaging. Taken together, our studies, for the first time, identify [2H9]-choline as a probe of CKα activity and highlight its ability to assess tumor burden and early response to therapy, which is a challenge in glioma imaging.
TMET-17. NOX2-INDUCED HIGH GLYCOLYTIC ACTIVITY CONTRIBUTES TO THE GAIN OF COL5A1-MEDIATED MESENCHYMAL PHENOTYPE IN GBM
Authors: Youngjoon Park, Minwoo Park, Junhyung Kim, Juwon Ahn, Jeongmin Sim, Ji-In Bang, Jinhyung Heo, Hyejeong Choi, Kyunggi Cho, Mihye Lee, Jong-Seok Moon, Jaejoon Lim
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma multiforme (GBM) is the most aggressive type of glioma and exhibits extensive heterogeneity and poor prognosis with a high recurrence rate. Among the genetic alterations in GBM with different phenotypic states, a mesenchymal subtype has been associated with a worse outcome in patients with GBM. The mechanisms for the gain of the mesenchymal subtype in GBM remain unclear. Our aim was to investigate whether NOX2-induced high glycolytic activity could contribute to the gain of the mesenchymal phenotype in GBM. We revealed that NOX2-induced high glycolytic activity can induce the gain of the COL5A1-mediated mesenchymal phenotype inGBM. Our findings will provide the molecular mechanism by which NOX2 contributes to the gain of mesenchymal phenotype in GBM.
EPID-14. EPIDEMIOLOGICAL SURVEY OF RADIATION-INDUCED MENINGIOMA: A SEER ANALYSIS
Authors: Jefferson Abaricia, Jashanjeet Matharoo, Charles Opalak, William Broaddus
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Radiation-induced meningioma (RIM) is a rare but serious consequence of cranial and cranio-spinal external beam radiation therapy (EBRT). While recent studies have characterized the epidemiological features of RIM in small populations or systematic reviews, none have studied RIM within a national database for a more generalizable description of this disease entity. The objective of this study was to identify and characterize the population with RIMs within a large national database. METHODS From the SEER Research Plus Nov 2020 (1975-2018) dataset, 56161 patients treated with EBRT for the following indications were identified: ocular/orbital tumors, brain/nervous system tumors, and leukemias. Next, a sub-population of 185 RIM patients, defined by histologically distinct precedent tumor treated with EBRT and a minimum 5-year latency from EBRT to meningioma, was identified. RIM prevalence, latency, pathologic behavior, and multiplicity were determined, and comparisons were made by sex, race, and original indication for EBRT. RESULTS The prevalence of RIM among the EBRT population was 0.33%. Among RIM patients, 41.62% were male and 84.32% were Caucasian. Average latency to RIM development was 23.39 ± 8.65 years, with no significant difference between sexes or races. Fourteen patients had multiple RIMs at diagnosis, while four patients experienced recurrent RIM. RIMs classified as “malignant” had a shorter latency (16.30 years) than “borderline” (26.11 years) or “benign” (23.36 years) RIMs. Of the most common original EBRT indications, precursor lymphoblastic leukemia (29.89 years) had longer latency to RIM than medulloblastoma (21.57 years) or astrocytoma (22.67 years); this may be explained by lower doses of radiation used for lymphoblastic leukemia treatment. CONCLUSION These data provide novel epidemiological information—most importantly, prevalence—of RIM in a nationwide population, and they suggest that RIM occurs in patients independent of sex or race. These findings will aid clinicians in explaining the risk of RIM development to patients undergoing EBRT.
NIMG-102. RAPNO-DEFINED SEGMENTATION AND VOLUMETRIC ASSESSMENT OF PEDIATRIC BRAIN TUMORS ON MULTI-PARAMETRIC MRI SCANS USING DEEP LEARNING; A ROBUST TOOL WITH POTENTIAL APPLICATION IN TUMOR RESPONSE ASSESSMENT
Authors: Anahita Fathi Kazerooni, Rachel Madhogarhia, Sherjeel Arif, Jeffrey B Ware, Sina Bagheri, Debanjan Haldar, Hannah Anderson, Ariana Familiar, Lorenna Vidal, Mariam Aboian, Philip B Storm, Adam C Resnick, Arastoo Vossough, Christos Davatzikos, Ali Nabavizadeh
Journal: Neuro-Oncology (2022)

Abstract Volumetric measurements of whole tumor and its components on MRI scans, facilitated by automatic segmentation tools, are essential to reduce inter-observer variability in monitoring tumor progression and response assessment for pediatric brain tumors. Here, we present a fully automatic segmentation model based on deep learning that reliably delineates the tumor components recommended by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group for evaluation of treatment response. Multi-parametric MRI (mpMRI) scans (T1-pre, T1-post, T2, and T2-FLAIR), acquired on multiple MRI scanners with different field strengths and vendors, for a cohort of 218 pediatric patients with a variety of histologically confirmed brain tumor subtypes were collected. The mpMRI scans were co-registered and manually segmented by experienced neuroradiologists in consensus to identify the tumor subregions including the enhancing tumor (ET), non-enhancing tumor (NET), cystic components (CC), and peritumoral edema (ED) regions. A convolutional neural network model based on DeepMedic architecture was trained using mpMRI scans as the inputs for segmentation of the whole tumor and subregions. The trained model showed excellent performance in segmentation of the whole tumor, as suggested by median dice of 0.90/0.85 for validation (n = 44)/independent test (n = 22) sets. ET and non-enhancing components (union of NET, CC, and ED) were segmented with median dice scores of 0.78/0.84 and 0.76/0.74 for validation/test sets, respectively. The automated and manual segmentations demonstrated strong agreement in estimating VASARI (Visually AcceSAble Rembrandt Images) MRI features with Pearson’s correlation coefficient R &amp;gt; 0.75 (p &amp;lt; 0.0001) for ET, NET, CC, and ED components. Our proposed automated segmentation method developed based on MRI scans acquired with different protocols, equipment, and from a variety of brain tumor subtypes, shows potential application for reliable and generalizable volumetric measurements which can be used for treatment response assessment in clinical trials.
CTNI-62. LONG-TERM EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS
Authors: Sébastien Perreault, Alexander Drilon, Ulrik N Lassen, Birgit Geoerger, Karsten Nysom, Ingrid Øra, Igor T Gavrilovic, Ricarda Norenberg, Vadim Bernard-Gauthier, Esther De La Cuesta, Theodore W Laetsch, François Doz, Cornelis M Van Tilburg
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Larotrectinib is a highly selective TRK inhibitor that demonstrated an objective response rate (ORR) of 30% and a 24-week disease control rate (DCR) of 73% across 33 evaluable adult and pediatric patients with TRK fusion primary CNS tumors, as of July 2020 (Doz et al, Neuro Oncol 2021). We report updated data on an expanded dataset. METHODS Patients with TRK fusion primary CNS tumors in two clinical trials (NCT02637687, NCT02576431) were included. Responses were investigator-assessed. RESULTS As of July 2021, 38 patients with TRK fusion primary CNS tumors (median age, 10.8 [range 1.3–79.0] years) were identified: high-grade glioma (HGG; n = 23), low-grade glioma (LGG; n = 9), and other (n = 6). Sixteen (42%) patients had ≥ 2 prior systemic therapies. ORR for 37 evaluable patients was 30% (95% confidence interval [CI] 16–47): three complete responses, eight partial responses, 21 stable disease (16 patients ≥ 24 weeks), and five progressive disease. For pediatric patients (n = 28), the ORR was 39% (95% CI 22–59). For pediatric patients with HGG and LGG, ORRs were 43% (95% CI 18–71) and 38% (95% CI 9–76), respectively. ORRs for patients with 0, 1, 2, and ≥ 3 prior therapies were 33%, 20%, 38%, and 38%, respectively. Median time to response was 1.9 months. The 24-week DCR was 73% (95% CI 56–86). Median duration of response (DoR) was not reached; 12-month DoR rate was 64%. Median progression-free survival was 16.5 months (95% CI 6.7–not estimable). Median overall survival (OS) was not reached; 24-month OS rate was 65%. Treatment duration ranged from 0.1+ to 38.7+ months. Treatment-related adverse events (TRAEs) were mostly Grade 1–2. No patients discontinued treatment due to TRAEs. CONCLUSION Larotrectinib demonstrated a high DCR, rapid and durable responses, and a manageable safety profile in patients with TRK fusion primary CNS tumors.
EPCO-42. HYPO-TRIMETHYLATION OF HISTONE H3 LYSINE 4 AND HYPER-DI/TRIMETHYLATION OF HISTONE H3 LYSINE 27 AS THE EPIGENETIC MARKERS OF POOR PROGNOSIS FOR PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA PATIENTS
Authors: Hoon Gi Kim, Young Zoon Kim
Journal: Neuro-Oncology (2022)

Abstract PURPOSE This study aimed to investigate the methylation status of major histone modification sites in PCNSL samples and examine their prognostic role in PCNSL patients. METHODS Between 2007 and 2020, 87 patients were histopathologically diagnosed as PCNSL, and they were treated with same protocol of high-dose methotrexate-based combination chemotherapy. Clinical data for PFS and OS was obtained from medical records retrospectively. Immunohistochemical staining for FFPE samples of PCNSL from pathological archives in our institute was performed for major histone modification site such as histone H3K4, H3K9, H3K27, H3K14, and H3K36. After detection of meaningful methylation site, we examine the histone modification enzyme which induce methylation or demethylation on each site using immunohistochemical staining. The meaningful immunoreactivity was validated with qRT-PCR and western blotting using fresh tissue of PCNSL under refrigerated state in N2O container. RESULTS Among 87 patients, 28 patients (32.2%) experienced recurrence or progression and 11 patients (12.6%) succumbed their disease during follow-up for 12 months or more. More frequent recurrences was found in hypomethylation of H3K4me3 (p=0.004), and hypermethylation of H3K27me2 (p&amp;lt; 0.001) and H3K27me3 (p=0.002). These factors were also statistically related with short PFS and OS in univariate and multivariate analysis. At the next step, histone modification enzyme inducing demethylation of H3K4 (LSD1/2, KDM5A-D, NO66), and methylation of H3K27 (EZH1/2) was immunohistochemically stained. Among them, the immunoreactivity of KDM5A was reversely associated with methylation status of H3K4me3 (R2=-1.243), and immunoreactivity of EZH2 was directly associated with methylation status of H3K27me2 (R2=0.988) and H3K27me3 (R2=1.139). These results was confirmed using RT-PCR and western blotting in fresh sample of PCNSL. CONCLUSION Our presenting study suggest that hypomethylation of H3K4me3, and hypermethylation of H3K27me2 and H3K27me3 could be associated with poor outcome of PCNSL patients. These relationship was modified by KDM5A as H3K4 demethylase and EZH2 as H3K27 methyltransferase.